Frontiers in toxicology最新文献

{"title":"Impact of intranasal cigarette smoke exposure on murine peripheral immune responses and lung pathology.","authors":"Laura G Bartlett, Yasmin Azizbayli, Amanda L Tatler, Adam J Watkins, Lucy C Fairclough","doi":"10.3389/ftox.2026.1884554","DOIUrl":"10.3389/ftox.2026.1884554","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is driven primarily by cigarette smoke exposure, yet modelling its immunopathogenesis in mice is complicated by systemic stress and welfare concerns associated with conventional exposure models. Here, we employ a refined intranasal cigarette smoke extract (CSE) model to examine pulmonary pathology and peripheral immune responses in male and female C57BL/6J mice. Repeated intranasal CSE exposure over 12 weeks was well tolerated and induced dose-dependent pulmonary neutrophilia, airway remodelling, and collagen deposition, with more pronounced pathology observed in female mice at higher exposure levels. In contrast, longitudinal multiparametric flow cytometric analysis revealed no consistent dose-dependent alterations in peripheral immune cell composition or activation, as confirmed by both conventional gating and unbiased clustering approaches. These findings demonstrate that COPD-like lung pathology can arise in the absence of overt systemic immune disruption and highlight the importance of lung inflammatory processes in disease development. This refined intranasal model provides a welfare-conscious platform for studying pulmonary immunopathology in COPD.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1884554"},"PeriodicalIF":5.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing skin sensitization prediction across activity cliffs: a comparative analysis of K-nearest neighbours vs random Forest.","authors":"Daniel C Ukaegbu, Karolina Kopańska, Peter Ranslow, Alexandra Maertens","doi":"10.3389/ftox.2026.1739746","DOIUrl":"10.3389/ftox.2026.1739746","url":null,"abstract":"<p><p>Computational models for skin sensitization prediction face critical challenges in handling activity cliffs, where structurally similar compounds exhibit different biological activities, limiting their regulatory applicability. This study systematically compared Random Forest (RF) and K-Nearest Neighbors (KNN) models using five molecular fingerprint approaches integrated with structural alerts and physicochemical properties. Models were developed using 1174 chemicals and evaluated across progressive feature integration levels: fingerprints alone, fingerprints with structural alerts, and fully integrated models. Performance was assessed using standard classification metrics and chemical similarity analysis for compounds with ≥70% Tanimoto similarity but discordant experimental outcomes. RF consistently outperformed KNN across all fingerprint approaches, achieving 81% balanced accuracy compared to (74%) in fully integrated models on the test set. Critically, RF demonstrated superior handling of activity cliffs compared to KNN. Substructure-based fingerprints (Avalon, PubChem and MACCS) consistently outperformed hash-based approaches (Morgan, Atom Pair), with Avalon showing optimal performance across metrics. SHAP interpretability analysis identified vapor pressure (VP) as the most consistently important physicochemical predictor and identified key reactive structural features aligning with known sensitization mechanisms. These findings provide evidence-based guidance for model selection when developing tools for skin sensitization and establish a systematic methodology for evaluating activity cliff performance that can be applied across other toxicological endpoints.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1739746"},"PeriodicalIF":5.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From sebocytes to skin engineering human sebaceous organoids within a reconstructed dermal matrix.","authors":"Tommaso Pusceddu, Luna Ardondi, Maria Pia Cavaleri, Lucia Sileo, Ilaria Vitali, Camila Quezada Meza, Michele Massironi, Marco Massironi, Barbara Zavan","doi":"10.3389/ftox.2026.1874806","DOIUrl":"https://doi.org/10.3389/ftox.2026.1874806","url":null,"abstract":"<p><strong>Introduction: </strong>Sebaceous gland biology depends on the integration of lipid metabolism, tissue architecture, and stromal interactions, yet most available <i>in vitro</i> systems fail to capture these features simultaneously. This work reports the generation of a functional three-dimensional (3D) sebaceous gland organoid embedded within a matrix and designed to reproduce the structural and functional properties of native sebaceous tissue.</p><p><strong>Methods: </strong>Using SZ95 sebocytes, we first established baseline responses in monolayer conditions using linoleic acid (LA) stimulation and pharmacological inhibition with retinol (RTN) and capsaicin (CPS). We then reconstructed a 3D organoid model in which a sebocyte-rich lipidogenic compartment was spatially organized within a matrix-supported microenvironment and associated with an outer stromal-like component. The model was evaluated using morphological, ultrastructural, and immunofluorescence analyses. To further define the mode of action of sebogenic activation in 3D, we analyzed genes related to extracellular matrix remodeling and tissue adaptation.</p><p><strong>Results: </strong>In both monolayer and 3D models, LA successfully induced a sebogenic program, characterized by increased lipid accumulation and upregulation of PPARγ and FABP4, which was effectively attenuated by RTN and CPS. The 3D model successfully maintained essential compartmentalization, epithelial identity, and stromal organization. Furthermore, transcriptional analysis revealed that LA stimulation in 3D induced coordinated changes in extracellular matrix and basement membrane genes (including MMP13, MMP16, and THBS2), indicating that sebogenesis is directly coupled with structural remodeling and microenvironmental adaptation.</p><p><strong>Conclusion: </strong>Altogether, these results demonstrate that we successfully reconstructed a functional <i>in vitro</i> model of a sebaceous gland organoid and established this platform as a relevant tool for mechanistic studies and for cosmetic screening of compounds targeting sebum regulation and sebaceous gland dysfunction.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1874806"},"PeriodicalIF":5.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and internal evaluation of a clinical prediction model for blood lead re-elevation in lead poisoning patients: a retrospective cohort study.","authors":"Jia Wu, Xuanqi Zhang, Sijie Hu, Xi Li, Tianwen Yang, Jie Yao, Yingjie He, Jian Gao, Yongyi Wang, Youchun Lei","doi":"10.3389/ftox.2026.1829277","DOIUrl":"10.3389/ftox.2026.1829277","url":null,"abstract":"<p><strong>Background: </strong>Blood lead can rise again after chelation therapy for lead poisoning, but few tools identify which patients are at highest risk. We developed and internally evaluated a model to predict this re-elevation from routinely collected clinical data.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of 163 patients hospitalized for lead poisoning at Chongqing Poison Control Center from 2014 to 2022. Blood lead re-elevation was ascertained from re-admission for lead poisoning after an initial response to chelation therapy. Logistic regression, random forest, and support vector machine models were evaluated. The dataset was randomly divided into training (70%, n = 114) and testing (30%, n = 49) sets. Model performance was assessed using area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, calibration, and decision curve analysis.</p><p><strong>Results: </strong>Among 163 patients, 59 (36.2%) experienced blood lead re-elevation. The cohort comprised 44 children (27.0%) and 119 adults (73.0%), and 111 patients (68.1%) were male. Pediatric patients had a higher re-elevation rate than adults (52.3% vs. 30.3%, p = 0.016). The random forest model showed the best internal test-set performance, with an AUC of 0.849, accuracy of 83.7%, precision of 77.8%, and recall of 77.8%. Important predictors included blood lead-to-season ratio, baseline-to-follow-up blood lead ratio, serum calcium-to-blood lead ratio, blood lead-to-hemoglobin ratio, and hemoglobin-to-AST ratio.</p><p><strong>Conclusion: </strong>An internally evaluated model can identify patients at higher risk of blood lead re-elevation after chelation therapy and could guide risk-based follow-up. External validation is needed before clinical use.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1829277"},"PeriodicalIF":5.1,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13466234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary heavy metal and trace element mixtures in chronic kidney disease: associations and implications for potential reverse causality.","authors":"Sisi Xie, Julien Vaucher, Maïwenn Perrais, Aurélien Thomas, Pedro Marques-Vidal","doi":"10.3389/ftox.2026.1892052","DOIUrl":"10.3389/ftox.2026.1892052","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic kidney disease (CKD) is a growing public health challenge, yet impaired kidney function may substantially alter urinary biomarker profiles, complicating their interpretation. We aimed to investigate the associations between urinary element concentrations and prevalent CKD, and to explore whether impaired kidney function and altered urinary excretion may contribute to reverse causality in the interpretation of urinary biomarkers.</p><p><strong>Methods: </strong>We conducted a cross-sectional analysis of urinary element mixtures and prevalent CKD among 6,192 adults (51.7% female; mean age 52.4 ± 10.7 years). Associations between urinary element concentrations and prevalent CKD were evaluated using logistic regression, restricted cubic spline models, and three mixture modeling approaches, including Bayesian kernel machine regression, weighted quantile sum regression, and quantile g-computation.</p><p><strong>Results: </strong>Participants with CKD exhibited lower urinary concentrations of selenium, molybdenum, cadmium, mercury, lead, and thallium, whereas urinary zinc concentrations were higher. Non-linear associations were observed for several elements. Across multiple mixture models, higher combined urinary element concentrations were consistently associated with lower odds of prevalent CKD. Cadmium, mercury, selenium, and thallium contributed most strongly to these inverse associations, whereas zinc showed a positive contribution.</p><p><strong>Discussion: </strong>These findings are unlikely to reflect protective effects and may instead reflect impaired urinary excretion resulting from kidney dysfunction. Our findings suggest that urinary elements in CKD reflect not only exposure but also disease-related alterations in renal excretory function. These findings highlight the potential for reverse causality when interpreting urinary elements as biomarkers or predictors of kidney outcomes.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1892052"},"PeriodicalIF":5.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: New methods and approaches in toxicology of emerging environmental contaminants.","authors":"Martin Ezechiáš, Michal Šíma, Jaroslav Semerád","doi":"10.3389/ftox.2026.1930982","DOIUrl":"https://doi.org/10.3389/ftox.2026.1930982","url":null,"abstract":"","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1930982"},"PeriodicalIF":5.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors associated with clinical severity in scorpion envenomation: a retrospective cross-sectional study in western Mexico between 2021 and 2025.","authors":"Héctor Andrés González-Ruiz, Selene Guadalupe Huerta-Olvera, José Alberto Plascencia-Jiménez, Erick Yoav Martínez-Gallegos, Jonathan Moisés Guzmán-Villalpando, Fanny Iraís Aviña-Galindo, Carla Arleth Ojeda-Vázquez, Eduardo Alfonso Hernández-Muñoz, Eugenio Vladimir Zavala-Sánchez, Hilda Vázquez-López, Alejandro Alagón, Christian Johana Baños-Hernández","doi":"10.3389/ftox.2026.1880720","DOIUrl":"10.3389/ftox.2026.1880720","url":null,"abstract":"<p><strong>Introduction: </strong>Scorpion envenomation is a major public health concern in Mexico. Although Q9 most of the approximately 300,000 annual cases are resolved without complications, a subset present with moderate or severe manifestations, and around 35 deaths are reported each year. Identifying factors associated with greater clinical severity may improve clinical assessment and management. Our objective was to evaluate factors associated with clinical severity among scorpion envenomated patients in western Mexico.</p><p><strong>Methods: </strong>We conducted a retrospective crosssectional study of patients with scorpion envenomation treated at an emergency department in Mexico between 2021 and 2025. Multivariable regression models were used to examine the association of demographic characteristics, time to medical care, and prehospital practices with clinical severity.</p><p><strong>Results: </strong>Of 3,145 patients, 32% were mild, 60% moderate, and 8.2% severe. Delayed access to medical care was associated with higher odds of moderate or severe envenomation whereas older age and higher body weight were protective. Overall use of traditional remedies, mainly milk and garlic, was not associated with severity. However, oral garlic use was associated with increased odds of moderate or severe envenomation and more frequent upper pharyngeal symptoms.</p><p><strong>Discussion: </strong>These findings suggest that delays in care-seeking are consistently associated with more severe clinical presentation, whereas age-related factors may confer relative protection. The observed association with garlic use, likely reflects differences in care-seeking behavior or symptom perception rather than a direct biological effect. Interventions should prioritize reducing delays to medical evaluation and addressing prehospital practices linked to delayed presentation.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1880720"},"PeriodicalIF":5.1,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering metabolomic dysregulation in <i>Lactuca sativa</i> caused by exposure to nano- and microplastics (NMPs).","authors":"María José Gómez-Ramos, Harshit Sahai, Chen Wang, Hui Li, Amadeo R Fernández-Alba, María Dolores Hernando Guil","doi":"10.3389/ftox.2026.1872426","DOIUrl":"10.3389/ftox.2026.1872426","url":null,"abstract":"<p><p>This work investigated the metabolic impact of nano- and microplastics (NMPs) in <i>Lactuca sativa</i> using controlled hydroponic exposures combined with non-targeted high-resolution mass spectrometry metabolomics. Polystyrene NMPs of four particle sizes (100, 200, 500, and 1000 nm) were tested across multiple concentrations. Multivariate analysis revealed clear metabolic discrimination between exposed and control plants, with smaller nanoparticles (100-200 nm) inducing the most substantial changes. Among the principal discriminant features, four were selected for in-depth characterization based on their statistical response, all consistently downregulated in NMP-exposed plants. α-Linolenic acid was confirmed at Schymanski Level 1, while three additional C18-class lipid-related features were annotated at Level 4. The four candidate metabolites point to disruption of polyunsaturated fatty acid (PUFA)-related pathways, with the C₁₈H₂₈O feature showing the strongest size-dependent response. In contrast, α-linolenic acid exhibited a more gradual response across particle sizes, suggesting a different interaction mechanism. Larger particles (500-1000 nm) induced markedly weaker effects, confirming the greater impact of smaller nanoparticles on PUFA downregulation. These findings illustrate the capability of HRMS-based untargeted metabolomics for evaluating NMP-induced metabolic disruption in food crops and its potential implications for plant health and food quality.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1872426"},"PeriodicalIF":5.1,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148690429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pesticide-specific case fatality and clinical outcomes among poisoning cases in Tanzania: a retrospective cross-sectional study.","authors":"Raphael Mwezi, Joseph Bukalasa, Fredrick Otieno, Rosevera Kombo, Grivin Ochola, Florida Muro, Anicet Honest, Sarah Urasa, Mark Davis, Michael Eddleston, Marieke Dekker, William Howlett, John-Mary Vianney","doi":"10.3389/ftox.2026.1882231","DOIUrl":"10.3389/ftox.2026.1882231","url":null,"abstract":"<p><strong>Background: </strong>Pesticide poisoning remains a major public health challenge in low- and middle-income countries, particularly where highly hazardous pesticides (HHPs) remain accessible and toxicovigilance systems are limited. Although Tanzania has recently initiated regulatory actions targeting HHPs, evidence regarding pesticide-specific mortality patterns and clinical outcomes remains scarce. This study assessed clinical outcomes, pesticide-specific case fatality, and mortality risk among pesticide poisoning cases reported in selected Tanzanian hospitals.</p><p><strong>Methods: </strong>A retrospective cross-sectional study was conducted using hospital records from Regional Referral Hospitals and District Hospitals in Arusha, Kilimanjaro, Morogoro, Iringa, and Mwanza regions between January 2017 and November 2024. Cases were identified through hospital poisoning records, emergency department registers, admission records, and medical files. Information on demographic characteristics, exposure type, pesticide category, and clinical outcomes was extracted using structured electronic forms. Descriptive statistics summarize poisoning characteristics and outcomes. Associations between demographic factors and clinical outcomes were assessed using chi-square tests. Binary logistic regression was used to identify predictors of mortality, and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported.</p><p><strong>Results: </strong>A total of 635 pesticide poisoning cases were included in the analysis. Most patients were male (64.1%) and aged 16-35 years (61.3%). Intentional exposure accounted for 70.2% of cases, while unintentional exposure represented 20.3%. Most patients fully recovered (67.9%; 95% CI: 64.1-71.4), whereas 18.4% (95% CI: 15.5-21.6) died following pesticide poisoning. Paraquat poisoning demonstrated the highest case fatality (93.3%), followed by glyphosate (45.5%) and tefluthrin (33.3%). Compared with lower-risk pesticide exposures, paraquat poisoning was associated with markedly increased odds of death (aOR = 21.5; 95% CI: 9.4-48.2), while glyphosate poisoning was associated with elevated mortality risk (aOR = 5.2; 95% CI: 1.8-14.6). Pesticides with case fatality exceeding 10% contributed 87.3% of all recorded deaths.</p><p><strong>Conclusion: </strong>Mortality following pesticide poisoning in Tanzania was strongly concentrated among a small number of highly hazardous pesticides, particularly paraquat. These findings support continued restriction and removal of highly hazardous pesticides, strengthening of pesticide-specific surveillance systems, improved clinical toxicology capacity, and enhanced poisoning prevention strategies. Continued monitoring will be important to evaluate the public health impact of recent pesticide regulatory reforms in Tanzania.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1882231"},"PeriodicalIF":5.1,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of <i>Saccharomyces cerevisiae</i> with cigarette smoke extract causes vacuolar fragmentation to combat cigarette smoke-induced cellular toxicity.","authors":"Aditya Shukla, Srimonti Sarkar, Alok Kumar Sil","doi":"10.3389/ftox.2026.1835170","DOIUrl":"10.3389/ftox.2026.1835170","url":null,"abstract":"<p><p>Exposure to cigarette smoke is one of the major risk factors for developing various diseases, such as chronic obstructive pulmonary disease (COPD), cardiovascular disorders, and cancer mediated via cellular oxidative stress and organelle dysfunction. To this end, the current study investigated how cigarette smoke extract (CSE) affects the vacuole structure and function in <i>Saccharomyces cerevisiae</i> as the vacuole plays a crucial role in handling oxidative stress-induced misfolded proteins. Our results indicated that CSE exposure causes transient vacuolar fragmentation peaking at 0.5 h, which correlates with reduced protein misfolding and improved cell survival. However, excessive fragmentation or vacuolar fusion sensitizes cells toward CSE-mediated cellular toxicity. To understand the underlying mechanism, this study provides the evidence of the involvement of PI(3,5)P2-Mediated signaling and phospholipase-driven remodeling of lipid moieties and suggests a role for mitochondrial function in CSE-mediated vacuolar fragmentation. Prolonged exposure to CSE impairs mitochondrial function and thus disrupts fragmentation, the adaptive survival strategy against cigarette smoke (CS). It results in proteostasis collapse, a characteristic shared by many inflammatory and degenerative disorders. Together, this study reveals a previously unrecognized cellular protection mechanism induced by CS and suggests avenues for further investigation for mitigating CS-mediated diseases.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1835170"},"PeriodicalIF":5.1,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}